ACRP3O is a circulating protein produced in adipose tissue. Plasma levels of ACRP3O are inversely related to adipose mass in humans and mice. ACRP3O levels in FVB mice increase from approximately 3 mg/mI at 1-week of age to 10 mg/mi and 30 mg/mI at 5-weeks of age in males and females, respectively. Several groups recently showed that ACRP3O is an important regulator of glucose homeostasis. The elevation of ACRP3O may therefore be associated with changes in glucose homeostasis that occur during sexual maturation. Furthermore, elevated levels of ACRP3O in adult females may be associated with their increased insulin sensitivity compared to males. The studies described in this proposal are focused on three specific aims. (1) Demonstrate the activity of a negative-feedback loop that regulates circulating levels of ACRP3O. Elevating ACRP3O exposure and studying the effects on endogenous ACRP3O production will test the hypothesis in the first aim. Feminization of adult males by neonatal castration may uncover the basis for the sexual dimorphism in circulating ACRP3O. (2) Demonstrate that the ACRP3O negative-feedback loop involves the hypothalamic-pituitary axis. Studying the effects of elevated ACRP3O on pituitary peptides as well as their effects on ACRP3O will test the hypothesis in the second aim and determine if the regulation of ACRP3O might involve a centrally mediated pathway. (3) Demonstrate that sexual maturation is associated with the rise of ACRP3O. Studying the rise of ACRP3O during puberty and comparing the timing with the onset of adulthood will test the hypothesis in the third aim. Accelerating or delaying the onset of adulthood by regulating the rise of ACRP3O during puberty might identify a novel role for ACRP3O in reproductive development.